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Cytokine Release Syndrome (CRS): IMDELLTRA®
can cause CRS including life-threatening or fatal reactions. In the
pooled safety population, CRS occurred in 57% (268/473) of patients
who received IMDELLTRA®, including 39%
Grade 1, 15% Grade 2, 1.7% Grade 3 and 0.2% Grade 4. Recurrent CRS
occurred in 24% of IMDELLTRA®-treated
patients including 20% Grade 1 and 3.4% Grade 2; one patient
experienced recurrent Grade 3.
Among the 268 patients who experienced CRS, 73% had CRS after the
first dose, 60% had CRS after the second dose, and 15% had CRS
following the third or later dose. Following the Cycle 1 Day 1, Day
8, Day 15 infusions, 24%, 8%, and 1% of patients experienced Grade ≥
2 CRS, respectively. From Cycle 2 onwards, 1.5% of patients
experienced Grade ≥ 2 CRS. Of the patients who experienced CRS, 31%
received steroids and 10% required tocilizumab. The median time to
onset of all grade CRS from most recent dose of IMDELLTRA®
was 16 hours (range: start of infusion to 15 days). The median time
to onset of Grade ≥ 2 CRS from most recent dose of IMDELLTRA®
was 15 hours (range: start of infusion to 15 days).
Clinical signs and symptoms of CRS included pyrexia, hypotension,
fatigue, tachycardia, headache, hypoxia, nausea, and vomiting.
Potentially life-threatening complications of CRS may include
cardiac dysfunction, acute respiratory distress syndrome, neurologic
toxicity, renal and/or hepatic failure, and disseminated
intravascular coagulation (DIC).
Administer IMDELLTRA® following the
recommended step-up dosing and administer concomitant medications
before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA®
infusions as described in Table 3 of the Prescribing Information
(PI) to reduce the risk of CRS. Administer IMDELLTRA®
in an appropriate healthcare facility equipped to monitor and manage
CRS. Ensure patients are well hydrated prior to administration of
IMDELLTRA®.
Closely monitor patients for signs and symptoms of CRS during
treatment with IMDELLTRA®. At the first
sign of CRS, immediately discontinue IMDELLTRA®
infusion, evaluate the patient for hospitalization and institute
supportive care based on severity. Withhold or permanently
discontinue IMDELLTRA® based on severity.
Counsel patients and caregivers to seek medical attention should
signs or symptoms of CRS occur.
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Neurologic Toxicity, Including ICANS: IMDELLTRA®
can cause life-threatening or fatal neurologic toxicity, including
ICANS. In the pooled safety population, neurologic toxicity occurred
in 65% of patients who received IMDELLTRA®, with Grade 3 or higher events in 7% of patients including fatal
events in 0.2%. The most frequent neurologic toxicities were
dysgeusia (34%), headache (17%), peripheral neuropathy (9%),
dizziness (9%), and insomnia (8%).
The incidence of signs and symptoms consistent with ICANS was 10% in
IMDELLTRA®-treated patients, including
events with the preferred terms: ICANS (4.7%), muscular weakness
(3.2%), cognitive disorder (0.6%), aphasia (0.6%), depressed level
of consciousness (0.4%), seizures (0.4%), encephalopathy (0.4%), and
leukoencephalopathy (0.2%). There was one fatal reaction of ICANS.
Recurrent ICANS occurred in 1.5% of patients. Of the patients who
experienced ICANS, most experienced the event following Cycle 1 Day
1 (2.5%) and Cycle 1 Day 8 (3.6%). Following Day 1, Day 8, and Day
15 infusions, 1.3%, 1.3% and 0.4% of patients experienced Grade ≥ 2
ICANS, respectively. ICANS can occur several weeks following
administration of IMDELLTRA®. The median
time to onset of ICANS from the first dose of IMDELLTRA®
was 16 days (range: 1 to 862 days). The median time to resolution of
ICANS was 4 days (range: 1 to 40 days).
The onset of ICANS can be concurrent with CRS, following resolution
of CRS, or in the absence of CRS. Clinical signs and symptoms of
ICANS may include but are not limited to confusional state,
depressed level of consciousness, disorientation, somnolence,
lethargy, and bradyphrenia.
Patients receiving IMDELLTRA® are at risk
of neurologic adverse reactions and ICANS resulting in depressed
level of consciousness. Advise patients to refrain from driving and
engaging in hazardous occupations or activities, such as operating
heavy or potentially dangerous machinery, until neurologic symptoms
resolve.
Closely monitor patients for signs and symptoms of neurologic
toxicity and ICANS during treatment with IMDELLTRA®. At the first sign of ICANS, immediately discontinue the infusion,
evaluate the patient and provide supportive therapy based on
severity. Withhold IMDELLTRA® or
permanently discontinue based on severity.
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Cytopenias: IMDELLTRA®
can cause cytopenias including neutropenia, thrombocytopenia, and
anemia. In the pooled safety population, based on laboratory data,
decreased neutrophils occurred in 16% of patients, including 9%
Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased
neutrophil count was 41 days (range: 2 to 306 days). Decreased
platelets occurred in 30% including 2.2% Grade 3 or 4. The median
time to onset for Grade 3 or 4 decreased platelets was 67 days
(range: 3 to 420 days). Decreased hemoglobin occurred in 56% of
patients, including 4.7% Grade 3 or 4. Febrile neutropenia was
reported as an adverse event in 1.5% of patients treated with
IMDELLTRA®.
Monitor patients for signs and symptoms of cytopenias. Perform
complete blood counts prior to treatment with all doses of
IMDELLTRA®, up through Cycle 5 Day 15 and
then prior to administration on Day 1 of each cycle starting with
Cycle 6. Based on the severity of cytopenias, temporarily withhold,
or permanently discontinue IMDELLTRA®.
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Infections: IMDELLTRA®
can cause serious infections, including life-threatening and fatal
infections.
In the pooled safety population, infections, including opportunistic
infections, occurred in 43% of patients who received IMDELLTRA®, including 14% Grade 3 or 4. The most frequent infections were
pneumonia (11%), urinary tract infection (9%), COVID-19 (6%), upper
respiratory tract infection (4.7%), respiratory tract infection
(4%), candida infection (2.1%), oral candidiasis (2.1%), and
nasopharyngitis (2.1%).
Monitor patients for signs and symptoms of infection prior to and
during treatment with IMDELLTRA® and
treat as clinically indicated. Withhold or permanently discontinue
IMDELLTRA® based on severity.
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Hepatotoxicity: IMDELLTRA®
can cause hepatotoxicity. In the pooled safety population, based on
laboratory data, elevated ALT occurred in 39% of patients who
received IMDELLTRA®, including 2.5% with
Grade 3 or 4 ALT. Elevated AST occurred in 43% of patients,
including 3.2% Grade 3 or 4. Elevated bilirubin also occurred in 16%
of patients, including 1.3% Grade 3 or 4. Liver enzyme elevation can
occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin prior to treatment with
IMDELLTRA®, and as clinically indicated.
Withhold IMDELLTRA® or permanently
discontinue based on severity.
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Hypersensitivity: IMDELLTRA®
can cause severe hypersensitivity reactions. Clinical signs and
symptoms of hypersensitivity may include, but are not limited to,
rash and bronchospasm. Monitor patients for signs and symptoms of
hypersensitivity during treatment with IMDELLTRA®
and manage as clinically indicated. Withhold or consider permanent
discontinuation of IMDELLTRA® based on
severity.
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Embryo-Fetal Toxicity: Based on its mechanism of
action, IMDELLTRA® may cause fetal harm
when administered to a pregnant woman. Advise patients of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with IMDELLTRA®
and for 2 months after the last dose.
